We are studying T cell antigen receptors (TCR) with the purpose of more fully understanding the requirements for their activation in an immune response. The two broad classes of TCR, alpha/beta TCR and gamma/delta TCR, are both under investigation. Our goal is to analyze these proteins biochemically and structurally. To do so requires that we produce sufficient amounts of protein for study and that we characterize the recombinant proteins for their appropriate functionality. Further study of their binding to ligands and of their three- dimensional structure by X-ray crystallography should lead to insights as to how these proteins function in the immune system. Unlike alpha/beta T cell receptors (TCRs) which recognize peptide antigens bound to major histocompatibility complex molecules (MHC), gamma/delta TCRs can directly recognize antigens in the form of intact proteins or non-peptidic compounds. About 5% of all peripheral blood T cells bear gamma/delta TCRs, most of which recognize a number of non-peptidic phosphorylated antigens. We have determined the structure of a human gamma/delta TCR isolated from a T cell clone that is activated by these phosphoantigens. The orientation of the variable (V) and constant (C) domains of the gamma/delta TCR is unique when compared to alpha/beta TCRs or antibodies. The complementarity-determining regions (CDRs) of the V domains exhibit a chemically reasonable binding site for a phosphorylated antigen, providing a possible explanation for the canonical usage of the Vgamma9 and Vdelta2 gene segments by receptors that recognize these compounds. Though the V domains of the gamma/delta TCR are similar in overall structure to the V domains of alpha/beta TCRs, the C domains of the gamma/delta TCR are strikingly different from those of alpha/beta TCRs.